ABSTRACT : Project 4 - Image-guided and model-based dosimetry for optimal PDT Project 4 focuses on novel technologies and tools for advancing the ability to image PDT dose or response to therapy at the levels of structural, functional and molecular interactions. The design is specifically on testing new approaches which link to the two clinical trial projects in skin and pancreas tumors. In aim 1, the range of technologies to quantify protoporphyrin IX (PpIX) in skin and the biophysical measures of blood flow, blood volume, oxygen saturation and collagen, are measured alongside high frequency US imaging. The focus is to establish a set of tools which allow intelligent combinations of enhancers to PpIX production in squamous cell and basal cell carcinoma, as being treated in Project 1. Aims 2 and 3 both focus on pancreas cancer (PanCa) working with Project 2, with an initial focus on using contrast-CT and US to track total blood volume in the tumors, prior to light therapy and in the response to treatment. Preliminary Phase 1 clinical data indicates that total blood volume, as estimated from contrast-CT, is the dominant dosimetric parameter which predicts lesion volume in the response, suggesting that PS measurement is less important than light dosimetry for this particular indication. This observation is followed up in a systematic series of studies in a large animal orthotopic tumor model in the rabbit pancreas, as a way to better simulate the clinical trial data using contrast CT. Aim 3 further develops our work on molecular imaging and the quantification of binding in vivo with project 3. Using a dual-tracer approach developed in the current funding period, we analyze the efficiency of binding-directed uptake of targeted nanocells, from in an orthotopic PanCa model. This quantification importantly allows separation of vascular leakage and interstitial transport from the more important information of binding and uptake in the cancer cells. We will test methods to improve interstitial transport and determine if the nanoconstructs are limited by binding or delivery in PanCa. In the end, this series of aims is both basic technology and methodology design and optimization with direct potential to translate into clinical trial use. It is our expectation that the results will be directly translate to impact the clinical trials within this proposed funding period, with technology transfer occurring through Core C to each of the other projects. RELEVANCE TO PUBLIC HEALTH Project 4 develops novel tools and techniques which will directly advance the ability to monitor treatment at the individual subject level. The resulting approaches can be used in humans during PDT treatment to plan dose delivery or monitor treatment to either better understand variation in response or to alter therapy to minimize the variation in response. Dosimetry planning and imaging, when done well, will improve therapeutic delivery.